Throughout life, old bone is continuously removed by bone-resorbing osteoclasts and replaced with new bone which is formed by osteoblasts. This cycle is called the bone-remodelling cycle and is normally highly regulated, i.e. the functioning of osteoclasts and osteoblasts is linked such that in a steady state the same amount of bone is formed as is resorbed.
The bone-remodelling cycle occurs at particular areas on the surfaces of bones. Osteoclasts which are formed from appropriate precursor cells within bones resorb portions of bone; new bone is then generated by osteoblastic activity. Osteoblasts synthesise the collagenous precursors of bone matrix and also regulate its mineralization. The dynamic activity of osteoblasts in the bone remodelling cycle to meet the requirements of skeletal growth and matrix and also regulate its maintenance and mechanical function is thought to be influenced by various factors, such as hormones, growth factors, physical activity and other stimuli. Osteoblasts are thought to have receptors for parathyroid hormone and estrogen. Ostoeclasts adhere to the surface of bone undergoing resorption and are thought to be activated by some form of signal from osteoblasts.
Irregularities in one or more stages of the bone-remodelling cycle (e.g. where the balance between bone formation and resorption is lost) can lead to bone remodelling dirorders, or metabolic bone diseases. Examples of such diseases are osteoporosis, Paget's disease and rickets. Some of these diseases are caused by over-activity of one half of the bone-remodelling cycle compared with the other, i.e. by osteoclasts or osteoblasts. In osteoporosis, for example, there is a relative increase in osteoclastic activity which may cause a reduction in bone density and mass. Osteoporosis is the most common of the metabolic bone diseases and may be either a primary disease or may be secondary to another disease or other diseases.
Post-menopausal osteoporosis is currently the most common form of osteoporosis. Senile osteoporosis afflicts elderly patients of either sex and younger individuals occasionally suffer from osteoporosis.
Osteoporosis is characterised generally by a loss of bone density. Thinning and weakening of the bones leads to increased fracturing from minimal trauma. The most prevalent fracturing in post-menopausal osteoporotics is of the wrist and spine. Senile osteoporosis, is characterised by a higher than average fracturing of the femur.
Whilst osteoporosis as a therapeutic target has been of, and continues to, attract a great deal of interest, tight coupling between the osteoblastic and osteoclastic activities of the bone remodelling cycle make the replacement of bone already lost an extremely difficult challenge. Consequently, research into treatments for prevention or prophylaxis of osteoporosis (as opposed to replacement of already-lost bone) has yielded greater results to date.
Oestrogen deficiency has been considered to be a major cause of post-menopausal osteoporosis. Indeed steroids including oestrogen have been used as therapeutic agents (New Eng. J. Med., 303, 1195 (1980)). However, recent studies have concluded that other causes must exist (J. Clin. Invest., 77, 1487 (1986)).
Other bone diseases can be caused by an irregularity in the bone-remodelling cycle whereby both increased bone resorption and increased bone formation occur. Paget's disease is one such example.
Lanthanum has been of prominence previously in medicine on account of its property of forming stable complexes with phosphate. This application has been evidenced in the treatment of hyperphosphataemia by application of lanthanum carbonate. U.S. Pat. No. 5,968,976 describes the preparation and use in a pharmaceutical composition of certain hydrates of lanthanum carbonate for the treatment of hyperphosphataemia.
Fernandez-Gavarron et al. (Bone and Mineral, 283-291 (1988)) report on studies into the incorporation of 140-lanthanum into bones teeth and hydroxyapatite in vitro. Whilst the depth of uptake varied from an estimated 5 to 15 μm (dependent on experimental conditions), the authors' conclusion was that an exchange of lanthanum for calcium in hydroxyapatite may provide for increased resistance to acidic induced dissolution. Based on this suggested increased acid-resistance, the authors suggest that lanthanum's clinical usefulness as an adjunct in treating diseases such as osteoporosis, root caries and alveolar bone resorption might be explored.
Vijai S. Shankar et al. (Biochemical and Biophysical Research Communications, 907-912 (1992)) report that extracellular application of Lanthanum (III) induced a concentration-dependant elevation of cytosolic calcium in osteoclasts. The authors suggested that the osteoclast calcium receptor may be sensitive to activation and inactivation by the trivalent cation Lanthanum.
Bernd Zimmermann et al. (European Journal of Cell Biology, 114-121 (1994)) report that lanthanum inhibited endochondral mineralization and reduced calcium accumulation in organoid cultures of limb bud mesodermal cells.